The purpose of the proposed studies is to assess the feasibility of developing a novel Neuropeptide Y (NPY) obesity treatment. Extensive preclinical and clinical studies indicate that NPY receptors are important mediators of appetite and obesity. The proposed Specific Aims will determine if chronic treatment with selective NPY Y2 or Y4 receptor agonists demonstrate significant anti-obesity activity in a well established rodent model of obesity. Preliminary studies indicate that proprietary Y2 (PD4048) and Y4 (PD4074) receptor agonists administered acutely demonstrated significant anti-obesity effects as judged by decreased food intake and enhanced metabolic rate. Additional Preliminary Studies demonstrate that acute co-administration of our selective Y2 and Y4 agonists resulted in a synergistic effect on food intake that was significantly greater than either drug administered alone. The proposed Specific Aims will take our preliminary studies to the logical next step by: 1) measuring longer-term anti-obesity effects after chronic drug administration, and 2) measuring chronic drug effects on an expanded range of obesity-related functional and behavioral measures as well as obesity-related co- morbidities. Our proposed Specific Aims are: Specific Aim 1: Determine the effect of chronic administration of the Y2- agonist PD4048 alone or the Y4-agonist PD4074 alone on food intake, body weight, energy expenditure, activity levels and regional fat/lean body mass in mice with high fat diet-induced obesity. Specific Aim 2: Determine the effects of PD4048 and PD4074 on obesity- related co-morbidities. Specific Aim 3: Determine the effect of combined administration of PD4048 and PD4074 on food intake, body weight, energy expenditure, activity levels and regional fat/lean body mass in high fat diet-induced obesity. Specific Aim 4: Determine the effects of combined PD4048 and PD4074 treatment on obesity-related co-morbidities. PUBLIC HEALTH RELEVANCE: In the present application, we propose studies to determine if our Y2- selective Neuropeptide Y agonist PD4024 and our Y4 selective Neuropeptide Y agonist PD4074 demonstrate an anti-obesity effect in a well established preclinical obesity model, mice fed a high fat diet. Mice, like humans, when fed a high fat diet become obese. The ability of PD4024 and PD4074 to decrease food intake, decrease body fat and to reverse obesity related co-morbidities such as insulin resistance and glucose intolerance will be determined.